Tocilizumab

Targets (1)

Identification

Name

Tocilizumab

Accession Number

DB06273

Type

Biotech

Groups

Approved

Description

Tocilizumab is a recombinant, humanized, anti-human interleukin 6 (IL-6) receptor monoclonal antibody that achieves a significant therapeutic response rate. The light chain is made up of 214 amino acids. The heavy chain is made up of 448 amino acids. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. FDA approved on January 8, 2010.

Tocilizumab (injection) was further approved by the FDA for the treatment of adults with giant cell arteritis, an inflammation of the blood vessels (vasculitis) in May, 2017. In a double-blind, placebo-controlled study, the patients achieved sustained remission from Week 12 through Week 52, which was associated with significant improvements in symptoms of giant cell arteritis, normalization of inflammatory laboratory tests and tapering the use of corticosteroids [2].

Pharmacology

Indication

Indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs). It is also indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) and active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older.

A decrease in C-reactive protein (CRP) was noted as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with both doses, however the greatest improvements were observed with 8 mg per kg tocilizumab. Similar pharmacodynamic changes were also observed in active polyarticular juvenile idiopathic arthritis and active systemic juvenile idiopathic arthritis patients.

Mechanism of action

Interleukin (IL)-6 plays essential roles not only in the immune response, but also in haematopoiesis and the central nervous system. Unregulated production of IL-6 has been found in chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA), systemic onset juvenile idiopathic arthritis (soJIA), Crohn's disease (CD), systemic lupus erythematosus (SLE) and vasculitis. Furthermore, IL-6 activities can explain many symptoms of these diseases. More importantly, serum levels of IL-6 are correlated with disease activity. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6-mediated signaling through these receptors.

When 4 mg/kg of tocilizumab was given every 4 weeks to RA patients, the pharmacokinetic parameters at steady state are as follows:
AUC = 13000 ± 5800 mcg∙h/mL;
Cmax = 88.3 ± 41.4 mcg/mL.
Tocilizumab accumulates following repeated doses. Furthermore, an increased body weight may increase plasma levels of tocilizumab.

When a dose of 8 mg/kg of tocilizumab is given to PJIA patients, the pharmacokinetic parameters are as follows:
AUC = 29500 ± 8660 mcg∙h/mL;
Cmax = 182 ± 37 mcg/mL.

When a dose of 8 mg/kg of tocilizumab is given to SJIA patients, the pharmacokinetic parameters are as follows:
AUC = 32200 ± 9960 mcg∙h/mL;
Cmax = 245 ± 57.2 mcg/mL.

Volume of distribution

In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In pediatric patients with PJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.

In pediatric patients with SJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.

Protein binding

Not Available

Metabolism

Not Available

Route of elimination

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation.

Half life

The half-life of tocilizumab is concentration-dependent. The concentration-dependent apparent half-life is up to 11 days for 4 mg/kg and up to 13 days for 8 mg/kg every 4 weeks in patients with RA at steady-state. The half-life in children with PJIA is up to 16 days. The half-life in pediatric patients with SJIA is up to 23 days.

Clearance

The clearance of tocilizumab decreases with increasing dose. At the 10 mg/kg single dose in RA patients, mean clearance was 0.29 ± 0.10 mL/hr/kg. The total clearance of tocilizumab is concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. At low concentrations, concentration-dependent nonlinear clearance is dominant. At high concentrations, linear clearance dominates. The estimated linear clearances for specific patient populations are as follows:
RA = 12.5 mL/h;
PJIA, pediatric patients = 5.8 mL/h;
SJIA, pediatric patients = 7.1 mL/h.